Identification of a 7H-pyrrolo[2,3-d]pyrimidin derivatives as selective type II c-Met/Axl inhibitors with potent antitumor efficacy

In this study, we reported the discovery of a novel type II c-Met/Axl Inhibitor, characterized by using 4-amino-7H-pyrrolo[2,3-d]pyrimidine as a hinge region binder. Through a systematic exploration of the structure-activity relationship, based on the clinically reported c-Met inhibitor BMS-777607, we identified the optimized compound 22a. 22a exhibited remarkable potency against c-Met and Axl kinases, with IC₅₀ values of 1 nM and 10 nM, respectively, and demonstrated over 100-fold selectivity to Other members of the TAM subfamily. Furthermore, compared to cabozantinib, compound 22a displayed superior anti-tumor proliferation activity across a range of solid tumors. 22a demonstrated excellent drug-like properties, achieving a bioavailability of 174.2 % in rats. In established MKN-45 and HCT116 xenograft tumor models, compound 22a achieved tumor growth inhibition (TGI) rates of 98.2 % and 87.2 %, respectively, at a dosage of 1 mg/kg. Taken together, compound 22a is a selective dual c-Met/Axl Inhibitor with significant potential as a clinical candidate.

Antitumor; Inhibitor; Rational design; c-Met.